alpha, beta-unsaturated gamma-lactone compounds and process for the production of same



United States Patent 0 3,331,837 a,B-UNSATUP.ATED 'y-LACTONE COMPOUNDS AND PROCESS FOR THE PRODUCTION OF SAME Hans-Giinter Lehmann, Berlin, Germany, assignor to Schering Aktiengesellschaft, Berlin, Germany No Drawing. Filed Oct. 30, 1964, Ser. No. 407,862

18 Claims. (Cl. 260239.57)

This invention relates to the preparation and use of 'y-lactones having the formula wherein A is hydroxyl and B is hydrogen or A and B together represent a CC bond, R is hydrogen or possibly a substituted or not substituted hydrocarbon group and R R and R are either individual substituted or not substituted hydrocarbon groups or jointly members of alicyclic ring systems.

A broad object of the invention is to provide a new method of making 'y-lactones from carboxylic acid esters of tertiary u-hydroxy ketones.

A narrower but more particular object is to provide 'y-lactones of lx-acyloxyketo steroids and the methods of preparation.

Another object is to provide various processes for the synthesis of the steroids of this invention, and to provide novel intermediates therefor.

Other objects of this invention are to provide 'y-lactones having antibacterial effects and 'y-lactones having antibiotic effects.

These new compounds in admixture with the usual excipients and carriers can be used for the treatment of mammals. Any of the conventional carriers can be used, such as water, oils, polyethyleneglycols, gelatine, lactose, starch, magnesium stearate, talcum, petroleum jelly and cholesterol.

The 'y-lactones of this invention exhibit antibacterial and antibiotic eiiects as disclosed by W. A. Sexton, Chemische Konstitution und biologische Wirkung, pp. 216-217.

The method of this invention contemplates reacting (a) carboxylic acid esters of tertiary a-hydroxy ketones where the acid components contain a CH group in u-position to the carboxyl ester group with (b) strong proton acceptors in (c) Water-free dipolar aprotic solvents. The reaction proceeds as follows:

Suitable aprotic solvents are disclosed by J. Miller and A. J. Parker, in the Journal of the American Chemical Society, vol. 83 (1961), p. 117. Examples of such aprotic solvents are dimethyl sulfoxide, dimethyl formamide, dimethylacetamide, N-rnethyl-a-pyrrolidone, tetramethylene sulfoxide, and tetramethylene sulfone.

Suitable proton acceptors for this reaction are metal hydrides, especially alkali metal hydrides such as sodium hydride, alkali metal amides, preferably sodium amide, alkali metal alcoholates such as sodium methylate, alkali 1 3,331,837 Patented July 18, 1967 or alkaline earth metal hydroxides such as sodium hydroxide and sodium metal.

Typical esters of tertiary u-hydroxy ketones having a CH group in a-position to the carboxyl group are:

5 A -pregnene-3 B,17otdiol-20-one-17 caproate,

21-desoxyprednisolone-dipropionate, 21-desoxyprednisone-acetate, 21-desoxyprednisone-propionate, 5a-pregnane-3fi,17a-diol-20-one-17-acetate, 5a-pregnane-3fl,17a-diol-20-one-17-propionate, 5 ,B-pre gnane-3 a,17u-diol-20 one-17-acetate, 5,8-pregnane-3a,17a-diol-20-one-17-propionate, 5a-pregnane-17a-ol-3 -20-dione-propionate, diphenyl-benzoyl-methyl-propionate, methyl-ethyl-acctyl-methyl-propionate.

The method of this invention produces the a,B-unsaturated 'y-lactone III in a two-stage process as shown above. The first stage is an intramolecular condensation (similar to an aldol condensation) between the keto group and the CH group in the tut-position to the carboxylic acid ester group of the starting material I. In the first stage ,G-hydroxy 'y-lactone II is produced and then is converted into the c p-unsaturated -lactone by removal of the 5- hydroxyl group.

By suitable variation of the external conditions, and especially by shortening the reaction time and 'by the use of alkaliand alkaline earth hydroxides as proton acceptors, the process of this invention can be performed in such a manner that the 8-hydroxy-'y'-lactone H is isolated as the principal product.

The process of this invention is chemically unique. The course of the reaction is surprising because the expected result would be a saponification of the ester group rather than lactone formation.

Of especially practical significance is the fact that the new process is applicable to a-acyloxyketo-steroids and is not in any manner alfected by the presence of other hydroxyl groups in the steroid structure, as shown by the following example:

L--OCOCH= A -pIegneneBB,17a-di0l-20'one-17-acetate 3,8,17a,20-trihydroxyA norcholenio acid 23-)l7-lacto11e 3B,17a-dihydroxyA -norcholadieuie acid 23-)17 lactone Typical reactions of the prior art preparation of steroids and the raw materials are disclosed by Kirk and Othmer, Encyclopedia of Chemical Technology, vol. 3, pp. 213-215 1949 and vol. 12, pp. 917-947 1954). The production of the particular raw material A this invention by reference to the preceding description.

The following preferred specific embodiments of the process are, therefore, merely exemplary and not to be considered limitative of the invention in any way what- SOCVFJ.

Example 1 60 ml. dimethyl sulfoxide are reacted under nitrogen hours at room temperature with 480 mg. sodium hydride and 3.75 'g, A -pregnene-3fi,l7a-diol-20-one l7-acetate with stirring. The mixture is then poured into water acidi-.

fied with acetic acid, filtered, washed with water, and dried. The yield is 3.5 g. crude 3,8,l7a-dihydroxy-A nor choladienic-acid-23 17-lactone. M.P. 247-253" C. For analysis it is recrystallized from ethyl acetate. M.P. 257 -259 C. 1 7 V 7 Example 2 ml. dimethylsulfoxide are reacted under nitrogen with 142 mg. sodium hydride and with l g. Set-pregnanc- 1701-01-3,20-dione-acetate 5 hours at room temperature under nitrogen with stirring. The product is worked up as in Example 1, chromatographed on silica gel and recrystallized from ethyl acetate. The yield is 0.26 g. 17u-hydroxy 3 OXO-A I1O1'-5a-Cl1lOleI]lC-21Cld-23 17-1210- tone. M.P. 233-234 C.

Example 3 10 ml. dimethylformamide are reacted under nitrogen with 355 mg. A pregame-3B,l7a-diol-20-one-l7-acetate and 31 mg. sodium hydride 5 hours at room temperature with stirring. The mixture is then poured into ice water acidified with acetic acid, filtered, washed with'water, and dried. The yield is 72% crude 3,8,l7a-dihydroxy-A nor-choladienic-acid-23e17-lactone.

Example 4 355 mg. A -pregnene-3B,17a-diol-2O-one-l7-acetate are dissolved in 5 ml. dimethyl sulfoxide and the solution then reacted under nitrogen with 80 mg. sodium methylate. The mixture is then stirred 5 hours under nitrogen at room temperature and after precipitation in water is worked up as above. The yield is 81% crude 3,8,l7a-dihydroxy-M -nor-choladienic-acid-23- 17-lactone.

Example 6 The reaction is performed as in Example 5, but with 30 mg. sodium instead of sodium methylate as condensation agent. After 5 hours the product is prepared as in Example 5 and is chromatographed on silica gel. The yield is 33% 3,B,17a-dihydroxy-A -nor-choladienic acid-23+ 17-lactone.

Example 7 390 mg. A -pregnene-3B,17a-diol-20-one-17-propionate (produced from A -pregnene-313,l7a-diol-20-one-3-acetate by esterification with propionic acid/propionic anhydride/ p-toluene-sulfonic acid, and partial saponification with methanolic HCl, M.P. 226228 C.) are dissolved in 5 ml. dimethylsulfoxide and then reacted under nitrogen added and themixture is stirred 5 hours at room temperature under nitrogen. The product is precipitated in water acidified with acetic acid, producing 360 mg. crude 35,17a-dihydroxy 22 methyl-A -nor-choladienicacid-2'3 17-lactone. M.P.v 215-228 C. After crystallization from ethyl acetate the yield is 170 mg. M.P. 237.5 239 C.

Example 8 400 mg. 3-enol-ethyl-ether of A -pregnene-17fl-ol-3,20- dione-l7-acetate are dissolved in 7 ml. dimethyl sulfoxide and the solution is then reacted under nitrogen with 26.4 mg. sodium hydride. The solution is stirred 5 hours at room temperature under nitrogen to produce the intermediate product 3 ethoxy 17B-hydroxy-A -norcholatrienic-acid-23 17-lactone. (This 3-alkyl-ether can j also be isolated in the usual manner. M.P. 184186 C.)

with 32 mg. sodium hydride. The mixture is stirred under nitrogen and after 15 minutes 1 ml. dimethyl sulfoxide is The product is reacted with 10 ml. dilute methanolic hydrochloric'acid, stirred 1 hour, poured into water and extracted with methylene chloride. The organic phases are washed with water and dried under vacuum. The residue is Washed with hexane and diisopropylether and recrystallized from ethyl acetate. The yield is mg. 17;; hydroxy 3 keto A 3 -nor-choladienic acid 23 17-lactone with a M.P. 205to 206 C. and with the formula Example 9 4.05 g. a benzoyl-a-phenyl-ethyl-acetate (produced from benzyl with methyl-magnesium-iodide and acetylation, M.P. 725-73 C.) are dissolved in 37.5 ml. di-

methyl sulfoxide, the solution then reacted under nitrogen solvent removed in vacuum. The residue is subjected to vacuumtractionation. The yield is 3 g. D,L-'y-methyl-fl,'y-

diphenyl-a-butenolide. B.P. mm Hg C.

fi Me I 0 Example 10 4.6 g. 1-acetoxy-l-acetyl-cyclohexane (B.P. Hg 7576 C.) are dissolved in 50 ml. dimethyl sulfoxide, the solution reacted under nitrogen with 0.66 g. sodium hydride, stirred overnight under nitrogen at room temperature, poured into ice water acidified with acetic acid, and extracted with methylene chloride. The product is washed with a little water, dried, evaporated to dryness and recrystallized from hexane. The yield is 1.7 g. B[1'- hydroxy cyclohexyl-( l) -cis-crotonyl-lactone. M.P. 45- 47 C. For analysis it is recrystallized from hexane. M.P.

49.5-5 1 C. The lactone can also be recrystallized from water.

Example 11 C Hs- 0 Example 12 2.64 g. acetoxy-benzoyl-diphenyl-methane (produced from benzyl with phenyl-magnesium-bromide and acetylation; M.P. 142-l43 C.) are stirred under nitrogen in 20 ml. dimethyl sulfoxide with 0.42 g. 50% sodium hydride suspended in oil hours at room temperature and then poured into ice water acidified with acetic acid. The resulting precipitate is filtered off, washed to neutrality, and dried. The crude product (1.8 g.) is recrystallized from ethyl acetate. The yield is 0.66 g. 3,-y,'y-triphenyl-a-butenolide. M.P. 195.5 to 196 C.

Example 13 3.6 g. 21 desoxyprednisolone 11,17 diacetate (M.P. 221-223 C.; produced from the free 21-desoxyprednisolone by esterification with glacial acetic acid and acetic anhydride and p-toluene-sulfonic acid) are dissolved in 85 ml. dirnethyl sulfoxide and stirred 5 hours at room temperature with 505 mg. of a 50% sodium hydride suspension in oil. The solution is then poured into ice water acidified with acetic acid and the resulting precipitate filtered otf, Washed with water, and dried, yielding 3.2 g. crude product.

This crude product is reacted in 15 ml. methanol with 0.15 ml. water and 0.01 ml. cone. hydrochloric acid by heating 5 minutes under reflux. The mixture'is then diluted with ether, extracted, washed with water and bicarbonate solution, dried, and the solvent evaporated to dryness. After recrystallization from ethyl acetate and acetone the yield is 1.2 g. 11B,l7a-dihydroxy-3-oxo-A -norcholatrienic acid-23 l7-lactone. M.P. 250.5 to 252 C.

Example 14 100 mg. A -pregnene-3fi,17a-diol-20-one 17 acetate powder are stirred with 1 mg. sodium hydroxide powder in 1.5 ml. dimethyl sulfoxide under nitrogen. After about 7 minutes the substance goes into solution. It is then immediately poured into ice water acidified with acetic acid, filtered off, washed with water, and dried. The yield is 96 mg. crude 313,l7a,ZO-trihydroxy-A -nor-cholenic-acid- 23 l7-lactone. After recrystallization from ethyl acetate/ methanol the product has a M.P. of 287 to 288 C.

Example 15 The method is followed as in Example 14, but 1 mg. sodium hydride is used instead of the sodium hydroxide. After about 7 minutes the mixture is poured into water to precipitate the crude product (95 rug.) from which an 85% yield of 3 6,17a-20-trihydroxy-A -nor-cholenic-acid- 23- l7-lactone is isolated. M.P. 287 to 288 C.

There is obtaned as a by-product a 15% yield of 35,170: dihydroxy-A -nor-choladienic-acid-23 17- lactone. M.P. 257 to 259 C.

Example 16 375 mg. A -Sa-pregnene-l7a-ol-3,20-dione-acetate powder are stirred with 3 mg. sodium hydroxide powder in 5 ml. dimethyl sulfoxide under nitrogen. The substance goes into solution after about 8 minutes. The mixture is immediately poured into ice water acidified with acetic acid, filtered, washed with water, and dried. The yield is 360 mg. crude l7a-20-dihydroxy-3-oxoeA -5a-nor-cholenic acid-23+ l7-lactone. M.P. 258 to 266 C. After recrystallization from ethyl acetate/ methanol the hydroXy-lactone melts at 266267 C.

Example 17 330 mg. finely pulverized acetoxy-benzoyl-diphenylmethane (prepared as in Example 12) and 40 mg. powdered sodium hydroxide are stirred in 5 m1. dimethylsulfoxide during 10 minutes at room temperature under nitrogen. The mixture is poured into ice water, extracted with ether and the extract then washed with water, dried, and evaporated to dryness under vacuum. The residue is recrystallized from methylene chloride/hexane and thereafter from diisopropyl ether, yielding D,L,fi-hydroxy- ,8,'y,'y-triphenyl-butano1ide. M.P. l54-155 C.

From the foregoing description one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly equitable, and intended to be, within the full range of equivalence of the following claims.

What is claimed is:

1. A compound selected from the group consisting of and ' 7 4. 17B hydroxy 3 keto M30422) nor choladie'nicacid-23+ l7-lactone. t

5 D,L 'y methyl 5, diphenyl or, butenolide. 6. ,3 [1 hydroxy cyclohexyl- (1')] cis crotonyllactone.

7. a methyl B [1' -"hydroxy cyclohexyl (1')]- cis-crotonyl-lactone.

8. B,' ,'y-triphenyl-a-butenolide.

9. 3l3,l7oc,20 trihydroxy A nor cholenic acid- 23 17-lactone. V

10. 17 a,20 dihydroxy 3 oxo A 5oz nor cholenic-acid-23- 17-lactone.

11. 11fi,l7 a dihydroxy 3 0x0 M 9 norcholatrienic-acid-23 17-lactone.

12. 3'- ethoxy 17B hydroxy L M nor cholatrienic-acid-23- 17-1actone.

13. 33,17a dihydroxy 22 methyl choladienic-acid-23 17-lactone.

8 14. D,L 8 hydroxy 5, triphenyl butanolide. 15. A process for the production of the compounds of claim 1 comprising reacting a 17-acyloxy-2O ketoderivative of the pregnane series with proton acceptors selected from the group consisting of metal hydrides, alkali metal amides, alkali metal alcoholates, alkali metal hydroxides, alkaline earth metal hydroxides and sodium in a water-free dipolar aprotic solvent.

16. The process of claim 15, wherein said aprotic solvent is dimethyl sulfoxide.

17. The process of claim 15, wherein said aprotic sol- I vent is dimethyl formamide.

18. The process of claim 15, wherein said strong proton acceptor is sodium hydroxide.

No references cited.

ELBERT L. ROBERTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,33l',837 July 18, 1967 Hans-Gunter Lehmann It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4 line 40 and column 5 line 24 for "benzyl", each occurrence, read benzil column 5, line 10, for "-cretonyl" read -crot0ny'1--- Column 6, lines 57 to 67 the lower left-hand portion of the formula should appear as shown below instead of as in the patent:

Signed and sealed this 20th day of August 1968 (SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 